The present invention provides compositions and methods for modulating the expression of C-reactive protein.
C-reactive protein (also known as CRP and PTX1) is an essential human acute-phase reactant produced in the liver in response to a variety of inflammatory cytokines. The protein, first identified in 1930, is highly conserved and considered to be an early indicator of infectious or inflammatory conditions. Plasma C-reactive protein levels increase 1,000-fold in response to infection, ischemia, trauma, burns, and inflammatory conditions. Since the biological half-life of C-reactive protein is not influenced by age, liver or kidney function or pharmacotherapy, it is a reliable biochemical marker for tissue destruction, necrosis and inflammation and its measurement is widely used to monitor various inflammatory states, angina pectoris, vascular insults, end-stage renal disease, rheumatoid arthritis, obesity and atherosclerosis (Arici and Walls, Kidney Int., 2001, 59, 407-414; Gabay and Kushner, N. Engl. J. Med., 1999, 340, 448-454; Highton et al., J. Rheumatol., 1985, 12, 871-875; Hulthe et al., Clin Sci (Colch), 2001, 100, 371-378; Lagrand et al., Circulation, 1999, 100, 6+96-102; Morrow and Ridker, Med. Clin. North Am., 2000, 84, 149-161, ix; Szalai et al., Immunol Res, 1997, 16, 127-136; Westhuyzen and Healy, Ann. Clin. Lab. Sci., 2000, 30, 133-143; Yudkin et al., Atherosclerosis, 2000, 148, 209-214).
Improved methods of quantifying C-reactive protein have led to increased application to clinical medicine including diagnoses of urinary tract infections (Arici and Walls, 2001, cited above), meningitis (Ruuskanen et al., J. Pediatr., 1985, 107, 97-100), neonatal sepsis, erythropoietin resistance (Barany, Nephrol. Dial. Transplant., 2001, 16, 224-227) and occult bacteremia, conditions in which C-reactive protein is usually elevated.
Structurally, C-reactive protein is a member of the pentraxin family of proteins, which are characterized by a cyclic pentameric structure and radial symmetry. The five identical 24-kDa protomers consist of 206 amino acids, and are noncovalently linked (Lei et al., J. Biol. Chem., 1985, 260, 13377-13383; Szalai et al., 1997, cited above). The genomic DNA sequence for human C-reactive protein has been reported by Lei et al. 1985, cited above, as have mutant forms of the protein (International Patent Publication No. WO 96/06624) and methods to deliver materials into cells using the mutant protein as a carrier (International Patent Publication No. WO 00/11207). Polypeptides corresponding to amino acids 174-185 of C-reactive protein having immunomodulatory activity are disclosed and claimed U.S. Pat. No. 5,783,179. Peptides corresponding to positions 62-71 of human C-reactive protein have also been studied for their ability to inhibit the activity of human leukocyte elastase and/or cathepsin G for the treatment of inflammatory conditions and these are disclosed in International Patent Publication No. WO 99/00418.
C-reactive protein binds to a broad range of cellular substances such as phosphocholine, fibronectin, chromatin, histones, and ribonucleoprotein in a calcium-dependent manner (Szalai et al., 1997, cited above). It is a ligand for specific receptors on phagocytic leukocytes, mediates activation reactions on monocytes and macrophages, and activates complement (Szalai et al., 1997, cited above).
The function of C-reactive protein is related to its role in the innate immune system. Similar to immunoglobulin(Ig) G, it activates complement, binds to Fc receptors and acts as an opsonin for various pathogens. Interaction of C-reactive protein with Fc receptors leads to the generation of proinflammatory cytokines that enhance the inflammatory response. Unlike IgG, which specifically recognizes distinct antigenic epitopes, C-reactive protein recognizes altered self and foreign molecules based on pattern recognition. C-reactive protein is therefore thought to act as a surveillance molecule for altered self and certain pathogens. This recognition provides early defense and leads to a proinflammatory signal and activation of the humoral, adaptive immune system. Thus, the C-reactive protein molecule has both a recognition function and an effector function.
The pharmacological modulation of C-reactive protein activity and/or its expression is therefore an appropriate point of therapeutic intervention in pathological conditions.
Strategies aimed at modulating C-reactive protein function by targeting protein levels have involved the use of antibodies, peptides and molecules that inhibit HMG-CoA reductase.
In a recent trial, it was demonstrated that lovastatin, an inhibitor of the enzyme HMG-CoA reductase, is an effective agent in reducing the risk of acute coronary events in participants with elevated C-reactive protein levels but no hyperlipidemia; the use of lovastatin resulted in a 14.8 percent reduction in median C-reactive protein levels after one year whereas no change was observed in the placebo group (Ridker et al., N. Engl. J. Med., 2001, 344, 1959-1965). Another statin, cerivastatin, has also been demonstrated to lower C-reactive protein levels in patients with hypercholesterolemia (Ridker et al., Circulation, 2001, 103, 1191-1193.).
However, there are currently no known therapeutic agents that effectively inhibit C-reactive protein levels and function. Consequently, there remains a long felt need for agents capable of effectively and selectively inhibiting C-reactive protein.